Much controversy surrounds the use of beta-agonists in obstructive lung disease. Regular beta2- agonist use in asthma results in tolerance to its effects and an increase in asthma-related deaths. Less is known about clinical outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis evaluates the long-term effect of beta2-agonist use on severe exacerbations requiring hospitalization or trial withdrawal, respiratory deaths, and total mortality in patients with COPD. Results for beta2-agonists are compared with results for anticholinergics and inhaled corticosteroids. Pooled results from randomized controlled trials show that anticholinergics, such as tiotropium and ipratropium, significantly reduce severe exacerbations and respiratory deaths compared with placebo. Conversely, beta2-agonists increase respiratory deaths, probably because of tolerance that develops to their bronchodilator and bronchoprotective effects. Anticholinergics significantly reduce exacerbations and total mortality compared with beta-agonists. The combination of the two bronchodilators is not more effective than anticholinergics alone in improving long-term clinical outcomes. Inhaled corticosteroids significantly reduce severe exacerbations and the decline in lung function over time, without affecting mortality. In conclusion, inhaled anticholinergic bronchodilators and corticosteroids should be used to improve long-term clinical outcomes in patients with COPD. beta-Agonists increase respiratory deaths in COPD, possibly as a result of poorer disease control.